Discovery approach

Kither Biotech focuses on the treatment of rare pulmonary diseases, including Cystic fibrosis (CF) and Idiopathic Pulmonary Fibrosis (IPF), two very different conditions for which there are very few pharmacological treatments with still an high unmet medical need. Kither has developed two proprietary chemical moieties that modulate signal transduction events controlled by PI3K enzymes.

As kinases, PI3K enzymes amplify extracellular signals inside the cell and control metabolism and proliferation. On these premises, Kither developed a small molecule inhibitor, KIT-CL27, that can block the enzymatic function of all members of the PI3K family. KIT-CL27 was optimised for inhaled treatment and offers a superior safety profile as a prodrug, this means that it is inactive in itself but can penetrate cell membranes and convert into an active compound within cells. The active compound is negatively charged, non-diffusible and rapidly secreted by the kidneys when it is carried in the blood (Campa et al., “Nature Communications” 2018).

This pharmacological profile allows it to restrict the anti-PI3K activity to the first targeted cells, thus drastically reducing the known toxic effects of PI3K inhibition. For example, systemic PI3K inhibitors alter the patient’s blood glucose levels, but KIT-CL27, when administered in the lungs, actively blocks the proliferation of IPF fibroblasts (Campa et al., “Nature Communications” 2018) but has no global effect on blood glucose. In IPF, alterations in PI3K signalling contribute to excessive fibroblast growth, which may limit pulmonary compliance and function. The ability of KIT-CL27 to act locally with limited side effects and systemic effects makes it an ideal molecule for the inhaled therapies used to treat this serious condition as observed in our preclinical studies (Campa et al., “Nature Communications” 2018).

In addition, the Kither team has discovered that PI3Ks are not only enzymes but also essential partners for other proteins. Past observations indicate that PI3Kgamma has two functions: on the one hand, it works as an enzyme, but on the other as the aggregator of a series of partners that control the cAMP signalling axis. Therefore, PI3Kgamma integrates two distinct signal transduction pathways: the classical PI3K pathway and the cAMP pathway (Lupieri et al., “J Cell Sci” 2018).

According to these findings, PI3Kgamma binds another kinase, called PKA, and restricts its function via a negative feedback loop involving type 3 and 4 phosphodiesterases (PDE3/4). Preclinical observations in support show that the loss of the scaffold function of PI3Kgamma leads to a lower PDE3/4 activity and, subsequently, a higher cAMP, which corresponds to bronchodilation and anti-inflammatory effects in lungs.

This resulted in the discovery of KIT-2014, a cell-permeable peptide containing the PI3Kgamma sequence that enables the association with PKA. When inhaled, KIT-2014 increases cAMP and brings about phosphorylation and the opening of the chloride channel CFTR. In cells and organoids of CF patients, where the CFTR mutations result in reduced chloride, treatment with KIT-2014 restores functions to an unprecedented level. Therefore, KIT-2014 offers three useful pharmacological properties: functioning as a bronchodilator, as an anti-inflammatory agent and as a CFTR opener